Project Summary/Abstract Cancer is one of the most desperate diseases due to the limited success of its treatment. However, Nature already provides clues for curing cancer, esp. for sexual hormone-related cancers, like liver cancer and breast cancer. Estrogen, the female dominating sexual hormone, shows opposite effects on the progression of liver cancer (preventing) and breast cancer (promoting), indicating that we may use the information from one cancer to cure the other cancer. In vitro studies show that estrogen signaling through estrogen receptor alpha (ER) in promoting the growth of breast cancer cells relies on forkhead box protein A (Foxa). We found recently that estrogen preventing liver cancer also depends on Foxa factors in vivo. Thus, I propose a comparative genomics study of Foxa/ER dual targets between liver cancer and breast cancer using in vivo models and human cancer tissues and cells to address the mechanisms of cancer progression and to identify novel therapeutic targets for both cancers. First, it is critical to investigate whether Foxa-dependent ER-mediated estrogen signaling also promote the tumor growth in mammary gland, which has never been studied in vivo. I will make mammary gland-specific Foxa1/2-deficeint mice with the Cre-loxP technology and then investigate Foxa/ER dual regulations during carcinogenesis. Functional genomics analysis including ChIP-Seq of Foxa1/2 and ER and gene expression profiling by microarrays and mRNA-Seq will be pursued to identify Foxa/ER dual targets in facilitating breast cancer. Our recent study also generated a list of Foxa/ER dual targets in preventing liver cancer with the same approach. Secondly, therefore, a comparative genomics study of Foxa/ER dual targets between liver cancer and breast cancer will be pursued to identify novel therapeutic targets for both cancers. The similar studies will also be applied to human cancer tissues and cell lines as well as normal controls. Lastly, tissue-differential regulations of Foxa/ER dual targets indicate the existence of the second layer of regulation beyond Foxa/ER. Thus, proteomics and epigenomics approaches will be pursued on above models to discover tissue-specific regulators of Foxa/ER. This will not only provide in vivo evidence for cancer genomics to guide cancer therapeutic studies, but will also address the mechanisms of genetic and epigenetic regulation of gene transcription of the same transcription factor that behaves/functions differentially in different tissues (liver versus mammary gland) or species (mouse versus human).